The present invention relates to synthesis and pharmaceutical compositions of novel 6-pyridylthio- and 6-pyridylseleno-substituted pyrimidine derivatives, useful for the treatment of infectious viral diseases, and for improving the efficacy of of anti-cancer therapeutics such as 5-fluorouracil in cancer therapy. With particular regard to antiviral activity, the compounds of this invention are useful in the treatment of Acquired Immunodeficiency Syndrome (AIDS) and related illnesses.
Acquired Immunodeficiency Syndrome is generally accepted to be the result of infection with a type of retrovirus termed the Human Immunodeficiency Virus (HIV). A number of strains or classes of HIVs have been identified, and it appears that HIVs are part of a broader family of retroviruses having similar genomes that are responsible for a wide range of diseases having diverse clinical manifestations.
In cases of AIDS, the infections are characterized by a marked depression in the hematological profile of the host and a general loss of the host immune response to invading pathogens, leaving the afflicted individuals extremely vulnerable to opportunistic infections by other microbes. In early stages of the infection, a number of less life-threatening manifestations have been reported and are generally referred to as AIDS-related complex.
At present, management of patients with HIV infections typically involves the administration of a pyrimidine nucleoside, such as, for example, azidothymidine (3'-azido-2',3'-deoxythymidine or "AZT"). Such chemotherapeutic agents function by inhibiting the reverse transcriptase of the HIV and reducing the cytopathic effects of the virus.
For further disclosures of pyrimidine nucleosides having antiviral properties and methods of synthesizing such compounds, see U.S. Pat. No. 3,282,921 issued to Verheyden et al. on Nov. 1, 1966; U.S. Pat. No. 3,687,931 issued to Verheyden et al. on Aug. 29, 1972; U.S. Pat. No. 3,755,295 issued to Verheyden et al. on Aug. 28, 1973; U.S. Pat. No. 3,775,397 issued to Etzold et al. on Nov. 27, 1973; U.S. Pat. No. 3,817,982 issued to Verheyden et al. on Jun. 18, 1974; U.S. Pat. No. 4,071,680 issued to Cook on Jan. 31, 1978; U.S. Pat. No. 4,093,715 issued to Lin et al. on Jun. 6, 1978; U.S. Pat. No. 4,128,639 issued to Lin et al. on Dec. 5, 1978; U.S. Pat. No. 4,210,638 issued to Greer on Jul. 1, 1980; U.S. Pat. No. 4,230,698 issued to Bobek et al. on Oct. 28, 1980; U.S. Pat. No. 4,331,662 issued to Eckstein et al. on May 25, 1982; U.S. Pat. No. 4,604,382 issued to Lin et al. on Aug. 5, 1986; U.S. Pat. No. 4,681,933 issued to Chu et al. on Jul. 1, 1987; Horwitz, Vol. 29, J. Org. Chem., pp. 2076-2078 (1964); Lin et al., Vol. 21, J. Med. Chem., pp. 109-112 (1978); Lin et al., Vol. 36, Biochem. Pharmacol., pp. 311-316 (1987); and Schinazi et al., Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract #369 (1987), herein incorporated by reference.
To date no compounds for the chemotherapy of AIDS have been discovered that are completely satisfactory or even as effective as AZT. Only a few others (3'-azido-2',3'-dideoxycytidine, 2',3'-dideoxyinosine, etc.) have even reached clinical trials. In view of the epidemic spread of the disease, there is a pressing need to find compounds that will be active against HIV during the latent stage of its life cycle to facilitate complete abrogation of the virus.
The treatment of AIDS with AZT has a number of drawbacks. In the first place it is only active against the HIV virus during the part of its life cycle during which it is replicating itself. AZT does not eradicate the virus as long as it remains latent, it only slows down the progress of the disease. It must be taken daily for an indefinite period of time, perhaps years, to keep the virus more or less in check. AZT is a toxic drug. In many cases, over a long period of time AZT causes damage to bone marrow and the hematopoietic system, and may give rise to neurological disorders. It would therefor be desirable to have other drugs available which are at least as good as AZT, which could be varied to avoid long-term side effects, and that would be more effective and less toxic.
In the field of cancer chemotherapy, the use of halogenated pyrimidine bases such as 5-fluorouracil (5-FUra), and halogenated pyrimidine nucleosides such as 5-fluoro-2'-deoxyuridine (5-FdUrd) as chemotherapeutic agents is well documented in the art (Heidelberger, C., in Antineoplastic and Immune Suppressive Agents Part II, A. C. Sartorelli and D. G. Jones ed.s, pp. 193-231, (Springer-Verlag, Heidelberg, 1975)). However the halogenated pyrimidine nucleosides are rapidly degraded to their respective pyrimidine bases, thereby reducing their effectiveness against the cancer tissue they are meant to treat. Moreover, cytotoxicity is caused by 5-FUra's toxic metabolites that are produced by the catabolism process.
These factors have limited the use of 5-FUra due to a low therapeutic index, leading to studies aimed at increasing its antitumor activity and decreasing its toxic effects on host tissue by combining 5-Fura with agents such as methotrexate (Cadman et al. (1979) Science 205:1135), N-(phosphonacetyl)-L-aspartate (Martin et al. (1989) Cancer 45:1117) allopurinol (Schwartz et al. (1980) Cancer Res. 40:1885), 5-benzylacyclouridine and AZT. Susceptible normal tissue can also be selectively rescued by the subsequent administration of large doses of uridine (Klubes et al. (1983) Cancer Res. 43:3182). However, this augmentative therapy is hampered by toxicity associated with the administration of high uridine dose, such as phlebitis and pyrogenic reactions.
It is a goal of this invention to provide a compound which is an effective antiviral agent, particularly against the retrovirus HIV.
It is another goal of this invention to provide an antiviral agent which is less toxic to a subject than AZT.
It is a further goal of the invention to increase the efficacy of 5-fluorouracil treatment in cancer therapy while decreasing host toxicity due to 5-fluorouracil and its metabolites.